# Neurotropic Viral Infection in CNS Aging and Alzheimer's Disease

> **NIH NIH R00** · UNIVERSITY OF NORTH CAROLINA CHARLOTTE · 2021 · $240,793

## Abstract

Project Summary
Alzheimer's disease (AD) is estimated to affect 5.3 million Americans currently and is expected to rise over the
next decade. Neuroinflammation is increasingly recognized as contributing to disorders of the central nervous
system (CNS) including AD. Microglial cell surface receptor TREM2 was recently identified from two
independent genome-wide association studies to contribute to the risk of developing AD, and previous studies
suggested that infectious burden may contribute to the etiopathogenesis of AD. I hypothesize that viral
encephalitis may enhance inflammatory events that accelerate the normal processes of CNS aging and
contribute to the development of AD pathology. This five-year project has three specific aims that use West
Nile virus (WNV) neuroinvasive disease as a model of viral encephalitis. During the K99 mentored phase of
this project, Aim 1 will identify mechanisms of microglial-mediated aging processes triggered by WNV
encephalitis using a TREM2-/- mouse model. I hypothesize that viral encephalitis triggers neuroinflammatory
processes that accelerate replicative senescence in microglia via telomere shortening and inflammatory
cytokine expression. Because TREM2 is critical in sensing environmental damage associated molecular
patterns, we expect that TREM2-/- microglia will be will be less effective in responding to neuronal damage
following viral encephalitis causing increased CNS aging. Aim 2, also during the K99 mentored phase, will
identify mechanisms of neuron-mediated aging processes triggered by WNV encephalitis. Data from the Klein
lab demonstrate that IL-1 receptor 1 (IL-1R1) signaling is essential for survival from acute neurotropic viral
infection. However, inflammatory cytokines including IL-1 and IL-8, which are upregulated via IL-1R1 signaling,
contribute to neuronal senescence via DNA damage. Experiments in this Aim will examine the role of IL-1R1
signaling following recovery from WNV encephalitis and during neuronal aging using IL-1R1-/- mice and in vitro
primary neuron culture models. During the R00 independent phase of this project, Aim 3 will explore the
impact of viral encephalitis on pathological tau accumulation. AD is defined by proteinaceous deposits
composed of Aβ and tau. Aβ is known to stimulate chronic inflammation; however, less is known about the role
of misfolded tau in the neuroinflammatory cascade, and even less is known is about how neuroinflammation
can contribute to tau deposition. I hypothesize that an acute episode of neuroinflammation caused by viral
encephalitis may predispose an individual to develop AD pathology. Experiments in this Aim will determine
whether viral encephalitis increases the rate at which transgenic mice harboring the Mapt P301L mutation
develop tau pathology, identify the impact of tau aggregates on the aging processes in primary microglia, and
determine whether IL-1β impacts tau aggregation propensity in primary neurons cultures from Mapt P301L
embryonic mi...

## Key facts

- **NIH application ID:** 10160734
- **Project number:** 5R00AG053412-05
- **Recipient organization:** UNIVERSITY OF NORTH CAROLINA CHARLOTTE
- **Principal Investigator:** Kristen Emily Funk
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $240,793
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160734

## Citation

> US National Institutes of Health, RePORTER application 10160734, Neurotropic Viral Infection in CNS Aging and Alzheimer's Disease (5R00AG053412-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10160734. Licensed CC0.

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